Joint disease is a common degenerative malady with a huge economic cost as well as a significant loss in quality of life for its sufferers. Joint disease manifests itself in many forms including arthritis, osteoarthritis and rheumatoid arthritis. These disorders have many pathologic events in common and they all result in pain, inflammation, and instability of the joint. In many cases, these disorders can lead to progressive degeneration of the joint with increasing discomfort and difficulty of use.
While any joint can be affected by joint disease, the most common types of joints affected are synovial joints. Synovial joints are marked by the articulation of separate bones that are held together by a fibrous cuff. In addition, the joint capsule is lined by a synovial membrane with the articulating surfaces of the bones covered by cartilage and the joint space filled with synovial fluid. Most joints of the body are synovial joints with the exceptions being fibrous joints, exemplified by the suture joints of the skull, and the cartilaginous joints, exemplified by the symphysis joint of the pelvis.
Though having a wide variation in form, all synovial joints have important structural features in common. These features include: the muscles, which are connected to the bones by tendons; the bursa, which allows the muscle to move smoothly over the joint; the ligaments, which connect the bones to each other and provide a framework to maintain the integrity of the joint; the synovial fluid, which lubricates the joint; the synovial membrane, or synovium, which encloses the interior space of the joint and produces the synovial fluid; and the capsule, which encloses the joint.
The effects of joint diseases such as arthritis, osteoarthritis and rheumatoid arthritis are quite profound. These effects include space loss, eburnation, cyst formation, osteophytosis, malalignment, fibrous ankylosis and in the spine, spondylosis. In addition, arthritis, osteoarthritis and rheumatoid arthritis are all marked by pain and swelling of the joint and are often accompanied by morning stiffness. Inflammatory osteoarthritis is also associated with joint inflammation and can lead to further pathological effects.
While the specific causes of joint diseases are as yet unidentified, the epidemiology is being pieced together. For instance, rheumatoid arthritis is thought to result from persistent inflammation of the joint. The inflammation may be the result of infection or injury. However, in rheumatoid arthritis, the inflammation continues after the infection has subsided or the acute injury has healed. Rheumatoid arthritis is marked by an infiltration of the joint by cells of the immune system, which causes a reaction called synovitis, and results in inflammation of the joint. Synovitis is followed by an abnormal growth of the synovial cells and a thickening of the synovium, which results in further swelling and increased pain in the joint.
Osteoarthritis occurs in about 10% of humans and in 50% of those over 60 years of age. Osteoarthritis is marked by a progressive breakdown of the cartilage and an inflammation of the synovium. Osteoarthritis usually affects the weight-bearing joints first and is known to move from joint to joint once the syndrome has been established. In addition osteoarthritis is also marked by inflammation and synovitis.
Treatments for joint diseases are generally limited to palliative treatments, which ease the pain and decrease the swelling, or invasive surgery to replace the joint. However, a cure or means of limiting the disease has yet to be identified.
Degenerative ligament disease is a form of joint disease, which is a common pathology of larger vertebrates. The most common manifestation of ligament disease in humans is disuse degeneration, partial and complete ligament rupture, and degeneration occurring after traumatic injury to the knee joint. Knee injuries are very common among active individuals. They are the most common injury in skiing and a prevalent injury in a host of other activities, including football, basketball, volleyball, soccer, tennis, and any other sport which requires rapid side-to-side movement. In addition to human joint injuries, joint injuries are common in a number of domestic animals. For instance lameness of the stifle, or rear knee joint in quadrupeds, is a common pathology of dogs, horses and other domestic animals. Stifle joint surgery is the most common elective surgery for dogs. While the knee is the most obvious joint displaying degenerative ligament disease, the disease is not limited to that joint. Other examples of joints that are disabled due to degenerative ligament disease are the acromioclavicular joint near the shoulder, the vertebral column, the hip, the foot and ankle, the hand, the tibiofibular at the lateral aspect of the knee, and the radioulnar joint at the elbow.
The knee joint is comprised of the femur, tibia and the patella. Holding these bones together is the work of important supporting tissues. These tissues are the anterior cruciate ligaments (ACL) and posterior cruciate ligaments (PCL) in humans, and the cranial and caudal cruciate ligaments (CCL) in dogs. In addition, there are other supporting tissues in the joint. These include collateral ligaments, meniscal ligaments, medial collateral ligament (MCL) and the patella tendon. Because of its position as the body's major load-bearing joint, the knee joint receives tremendous stress every day with little opportunity for normal rest. Consequently, this may be one of the reasons that the knee is so susceptible to ligament disease.
In many cases, individuals do not know they have ligament damage until they begin to feel instability in the knee. Frequently, this instability is also accompanied by partial or total rupture of the anterior or posterior cruciate ligaments. After instability has ensued, there are only two treatments: surgery and incapacitation. Both surgery and incapacitation have the same effect; loss of mobility and disuse of the knee joint. Unfortunately, joint disuse is implicated in further joint degeneration.
Ligaments, like other connective tissue, are thought to follow a process of remodeling. Ligaments are a specialized connective tissue, which guide normal joint motion and limit abnormal joint motion. A decline in the normal mechanical behavior of ligaments can result in increased joint laxity, which in turn is associated with degenerative joint disease and osteoarthritis (Daniel et al., 1994). Ligaments are composed primarily of fibroblasts, collagen fibrils, and an additional interfibrillar matrix. Type I collagen is the most abundant collagen in tendon and ligament extracellular matrices. Type I collagen is present in the form of collagen fibrils, which are long filamentous structures that aggregate to form collagen fibers that in turn combine to form fascicles (Birk and Trelstad, 1986, Kastelic et al., 1978, Provenzano et al., 2001).
Collagen fibers, the primary structural element of ligament, are composed of long collagen fibrils that are primarily aligned along the long axis of the tissue but show substantial overlapping and interweaving (Brodsky et al., 1982, Danylchuk et al., 1978, Provenzano et al., 2001). This microstructural organization of collagen fibrils within and across collagen fibers allows the fiber to provide the tissue's exceptional tensile strength under normal physiologic conditions (Barenberg et al., 1978, Viidik, 1972). During disuse, however, the tensile strength of ligament is greatly reduced (Vailas et al., 1990, Vanderby et al., 1990, Woo et al., 1987). Vanderby et al. and Woo et al. have demonstrated that short periods of joint disuse result in substantial loss of tissue stiffness and reduction of load-bearing capacity. After only seven days of disuse through hindlimb unloading, rat medial collateral ligament (MCL) ultimate stress is decreased by more than 25% (Vanderby et al., 1990), while nine weeks of joint immobilization decreases tissue stiffness and reduces ultimate load in rabbit MCLs to 31% of controls (Woo et al., 1987).
Ligaments and tendons, like other connective tissues, modulate their mechanical properties and biochemical composition in response to loading. Microscopic examination of ligament morphology from tissues unloaded in organ culture or from immobilized joints reveals collagen matrix disorganization and abnormal cellular distribution (Akeson et al., 1984, Thielke et al., 1994). In addition, biochemical analysis of ligaments from immobilized joints reveals a reduction in total collagen, increased collagen turnover, increased collagen synthesis and degradation rate with the degradation rate exceeding the synthesis rate (Akeson et al., 1987, Amiel et al., 1983).
Although it is generally accepted that musculoskeletal tissues are mechanotransductive and able to respond to alterations in their loading environment by adaptation of the load-bearing tissue, little is known about the process of ligament modeling and remodeling. Ligaments are required to adapt precisely to joint growth during development, and to respond to joint stresses after maturity. Ligaments when compared to tendons, have more numerous and larger cells, higher DNA content, a larger amount of reducible collagen cross-links, and more type III collagen (Amiel et al., 1984, Petersen and Tillman, 1999). This suggests that ligaments are more metabolically active and have greater adaptive potential than tendons. Normal noninflammatory adaptive remodeling of ligament collagen is thought to occur by intracellular digestion with lysosomal cathepsins, such as cathepsin B and L, after phagocytosis of extracellular matrix collagen by fibroblasts. In contrast, rapid inflammatory remodeling of collagen appears to be mediated by matrix metalloproteinase enzymes (Everts et al., 1996). However, the loss of collagen mass during remodeling of the CCL after rupture does not appear to be mediated by matrix metalloproteinases (Amiel et al. 1989, Spindler et al., 1996).
Rupture of the cranial cruciate ligament (CCL) is a common and crippling problem in dogs, and causes progressive deterioration in limb function over time (Muir et al., 2002). Progressive osteoarthritis and persistent lameness are commonplace, even with surgical treatment (Innes et al., 2000). Furthermore, partial CCL tears that are treated medically with rest and analgesics often progress to complete tears over time. Complete rupture of the CCL occurs because of progressive structural failure over a period of time in most affected dogs, many of which have bilateral disease (Muir et al., 2002, Bennett et al., 1988). Tissue changes that have been identified during progressive CCL rupture in dogs include loss of ligament fibroblasts, transformation of fusiform ligament fibroblasts to an ovoid or spheroid phenotype, and disruption of the normal hierarchical architecture of Type I collagen within the extracellular matrix, including loss of crimp and disruption of ligament fascicles (Vasseur et al., 1992, Whitehair et al., 1993). Dogs with early cruciate disease usually have a stable stifle joint on physical examination because most of the CCL must be ruptured for joint instability to be detected clinically (Heffron and Campbell, 1978). Although various risk factors for CCL rupture have been identified, including age, body weight, and dog phenotype (Duval et al., 1999, Morris and Lipowitz, 2001, Hayashi et al., 2003, Hayashi et al., 2003, Vasseur et al., 1985), the disease mechanism resulting in CCL rupture in dogs is poorly understood.
The conventional wisdom on the epidemiology of ligament disease in humans is that it is the result of acute trauma. In one such instance the ligaments are injured when the lower leg is rotated rapidly with the joint at 20-50 degrees of flexion. Instances of such stress on the knee occur during skiing, playing basketball, volleyball, or other similar activities. In other cases acute knee injury can result from simply taking a bad step on uneven ground. While acute injury may simply be the result of a single traumatic episode, it may also result from sub-clinical ligament degeneration that puts the joint at risk. Further, even without prior disease, acute injury may result in ligament rupture that is either partial or complete. Even when partial, because the treatment is surgical intervention followed by rest, there is a risk of ligament disuse degeneration. However, joint disuse also presents the prospect of continued degeneration of the joint through unidentified mechanisms.
While several enzymes are thought to be responsible for ligament remodeling in a healthy state, the pathologic mechanism leading to ligament degeneration as exhibited in both dogs and in humans during disuse and recovery from disuse or a traumatic injury has not been elucidated. However, this pathologic progress presents an important pathway for identifying degenerative ligament disease and for prophylactically treating ligament degeneration resulting from either pathological causes or from acute injury.
Therefore, it is desirable to find a method of diagnosing ligament disease and a method of treating ligament disease such that radical intervention such as surgery is not necessary and bed rest or disuse degeneration does not become part of the recovery process.